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Claudin-6-specific immunoreceptors and T cell epitopes

a technology of immunoreceptors and t cells, applied in the field of claudin-6-specific immunoreceptors and t cell epitopes, can solve the problems of significant morbidity and mortality in immune compromised individuals such as transplant recipients or aid patients, and the inability to systemically correlate immunoreactivity with clinical outcomes, and achieve the effect of minimizing adverse effects

Active Publication Date: 2019-08-06
BIONTECH CELL & GENE THERAPIES +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach allows for the selective targeting and destruction of cancer cells expressing CLDN6, potentially improving the efficacy of immunotherapy by expanding antigen-specific T cells and enhancing treatment options for various cancers.

Problems solved by technology

However, in most cases detected immune responses cannot systemically be correlated with clinical outcomes (Curigliano, G. et al.
While CMV infection and reactivation of endogenous latent viruses is controlled by the immune system in healthy individuals, it results in significant morbidity and mortality in immune compromised individuals such as transplant recipients or AIDS patients.
Especially in other cancers than melanoma, it is difficult to obtain such tumor-reactive TILs.
Furthermore, repeated in vitro stimulation and clonal expansion of normal human T lymphocytes results in progressive decrease in telomerase activity and shortening of telomeres resulting in replicative senescence and decreased potential for persistence of transferred T cells (Shen, X. et al.
However, hitherto no HLA-A*2-restricted CLDN6 T cell epitopes and T cell receptors targeting CLDN6 have been described and it is unknown whether CLDN6 expressing cancer cells can be targeted in vivo by immunotherapies involving T cells using active or passive immunization approaches.

Method used

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  • Claudin-6-specific immunoreceptors and T cell epitopes
  • Claudin-6-specific immunoreceptors and T cell epitopes
  • Claudin-6-specific immunoreceptors and T cell epitopes

Examples

Experimental program
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example 1

and Methods

[0426]Cell Lines and Reagents

[0427]The human chronic myeloid leukemia cell line K562 (Lozzio, C. B. & Lozzio, B. B (1975), Blood 45, 321-334) was cultured under standard conditions. K562 cells stably transfected with HLA-A*0201 (Britten, C. M. et al. (2002), J. Immunol. Methods 259, 95-110) (referred to e.g. as K562-A*0201) were used for validation assays. The primary human newborn foreskin fibroblast cell line CCD-1079Sk (ATCC No. CRL-2097) was cultured according to the manufacturers' instructions.

[0428]The human CLDN6 expressing ovarian carcinoma cell line OV-90-SC12 was used for in vivo validation of the CLDN6-CAR.

[0429]The culture medium for PA-1-SC12_A0201_luc_gfp_F7 is composed of 86% RPMI 1640+ Glutamax (Co. Gibco, Cat-No. 61870), 10% FCS (Co. Biochrome, Cat-No. S0615), 1% Sodium Pyruvate (100 mM) (Co. Gibco, Cat-No. 11360), 1% MEM Non-Essential Amino Acids Solution (100×) (Co. Gibco, Cat-No. 11140), 2% Sodium Bicarbonate 7, 5% solution (Co. Gibco, Cat-No. 25080).

[...

example 2

of High-Affinity HLA-A*02-Restricted Murine TCRs Specific for Claudin-6

[0475]We validated the immunogenic potential of CLDN6 in A2 / DR1 mice by repetitive intranodal immunization with CLDN6 encoding IVT-RNA and used spleen cells of these mice for isolation of CLDN6-specific T cells and subsequent cloning of the corresponding TCR genes (FIG. 5). Spleen cells of immunized mice were analyzed for the successful induction of CLDN6-specific T cells and their reactivity against predicted HLA-A*02 binding CLDN6 peptides ex-vivo by IFNγ-ELISPOT assay (FIG. 6).

[0476]Significant frequencies of CLDN6-specific T cells could be induced In all three mice by RNA immunization, whereas T cell reactivity was focused on two CLDN6 peptides predicted, that were with the best HLA-A*02 binding score (Cl6-A2-1 and Cl6-A2-2).

[0477]For isolation of CLDN6-specific T cells, spleen cells of immunized mice were restimulated in-vitro and sorted by flow cytometry based on the activation-induced upregulation of CD137...

example 3

ve Testing of Murine TCRs Specific for CLDN6 91-99

[0480]In total six murine TCRs were identified that all recognize the HLA-A*02-restricted epitope CLDN6-91-99. In order to confirm that this epitope is naturally processed and presented by endogenously CLDN6 expressing tumor cell lines and to evaluate the potential of the identified murine TCRs to mediate killing of such cells a luciferase-based cytotoxicity assay was performed. Human preactivated CD8+ T cells were transfected with TCR RNA and surface expression was analyzed by flow cytometry (FIG. 9). All murine TCRs were expressed on a high percentage of human CD8+ T cells after RNA transfer as indicated by staining with an fluorochrome-conjugated antibody specific for the constant domain of the murine TCR-β chain. TCR-transfected T cells were subjected to luciferase-based cytotoxicity assay together with the CLDN6-expressing tumor cell lines PA1 (teratoma) and NIH-Ovcar3 (ovarian carcinoma). The CLND6-negative breast cancer cell l...

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Abstract

The present invention provides Claudin-6-specific immunoreceptors (T cell receptors and artificial T cell receptors (chimeric antigen receptors; CARs)) and T cell epitopes which are useful for immunotherapy.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS[0001]This application is a U.S. National Phase Application under 35 U.S.C. § 371 of International Patent Application No. PCT / EP2015 / 056899, filed Mar. 30, 2015, and claims the priority of PCT / EP2014 / 000868, filed Apr. 1, 2014 and PCT / EP2014 / 072864, filed Oct. 24, 2014, all of which are incorporated by reference in their entireties. The International Application was published on Oct. 8, 2015 as International Publication No. WO 2015 / 150327 A1.TECHNICAL FIELD OF THE INVENTION[0002]The present invention relates to the provision of Claudin-6-specific immunoreceptors (T cell receptors and artificial T cell receptors (chimeric antigen receptors; CARs)) and T cell epitopes which are useful for immunotherapy.BACKGROUND OF THE INVENTION[0003]The evolution of the immune system resulted in vertebrates in a highly effective network based on two types of defense: the innate and the adoptive immunity.[0004]In contrast to the evolutionary ancient innat...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07K14/47C07K14/74C07K16/28C07K14/705C07K14/725A61K39/00G01N33/50G01N33/569G01N33/574A61K38/00A61K35/17
CPCC07K14/4748C07K14/7051C07K14/70521C07K14/70539C07K16/28G01N33/505G01N33/56972G01N33/574A61K39/0011C07K2319/30A61K35/17A61K38/00A61K39/00A61K2039/5156A61K2039/5158C07K2317/56C07K2317/622C07K2319/02C07K2319/03A61K39/4631A61K39/464499A61K39/4611A61K39/464402A61K39/4632C07K16/3007C07K2319/33A61K2239/59A61K2239/31A61K2239/38A61P35/00A61P37/04
Inventor SAHIN, UGURTURECI, OZLEMSIMON, PETRAOMOKOKO, TANAHOFF, HOLGERVOSS, RALF-HOLGERBREITKREUZ, ANDREAHOBOHM, KATHLEENMROZ, KAROLINA ANNA
Owner BIONTECH CELL & GENE THERAPIES
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